Tailored Reconstituted Lipoprotein for Site-Specific and Mitochondria-Targeted Cyclosporine A Delivery to Treat Traumatic Brain Injury

Abstract

The secondary damage in traumatic brain injury (TBI) can lead to lifelong disabilities, bringing enormous economic and psychological burden to patients and their families. Mitochondria, as the core mediator of the secondary injury cascade reaction in TBI, is an important target to prevent the spread of cell death and dysfunction. Thus, therapeutics that can accumulate at the damaged sites and subsequently rescue the functions of mitochondria would largely improve the outcome of TBI. Cyclosporine A (CsA), which can maintain the integrity of mitochondrial function, is among the most promising neuroprotective therapeutics for TBI treatment. However, the clinical application of CsA in TBI is largely hindered because of its poor access to the targets. Here, to realize targeted intracellular CsA delivery, we designed a lipoprotein biomimetic nanocarrier by incorporating CsA in the core and decorating a matrix metalloproteinase-9 activatable cell-penetrating peptide onto the surface of the lipoprotein-mimic nanocarrier. This CsA-loaded tailored reconstituted lipoprotein efficiently accumulated at the damaged brain sites, entered the target cells, bound to the membrane of mitochondria, more efficiently reduced neuronal damage, alleviated neuroinflammation, and rescued memory deficits at the dose 1/16 of free CsA in a controlled cortical impact injury mice model. The findings provide strong evidence that the secondary damages in TBI can be well controlled through targeted CsA delivery and highlight the potential of a lipoprotein biomimetic nanocarrier as a flexible nanoplatform for the management of TBI.

Atomic Engineering of Clusterzyme for Relieving Acute Neuroinflammation through Lattice Expansion

“…Immunohistochemistry shows that large amounts of cytokines are released after brain injuries, while Au 24 Ag 1 can remarkably reduce TBI-induced cytokines to nearly normal levels (Figure i–l), therefore alleviating inflammation. Acute neuroinflammatory responses are also prevented via inhibiting micoglia and astrocytes activation at the early stage (Figures S17 and S18), coforming to the pathology of TBI. − Besides this, tissue apoptosis further confirmed the recovery effects of Au 24 Ag 1 on cell apoptopsis in brain tissues (Figure S19).…”

Mitochondrial dysfunction and potential mitochondrial protectant treatments in tendinopathy

“…118 Cyclosporin A (CsA), a cyclic peptide, has been shown to be an inhibitor of the mPTP complex and can prevent cell death caused by oxidative stress. 119 It has been described in a wide variety of experimental models of ischemiareperfusion injury, 120 collagen VI myopathies, 121 and traumatic brain injury 122 to correct mitochondrial dysfunction and apoptosis, suggesting its potential as a therapy for tendinopathy.…”

Activatable cell-penetrating peptides: 15 years of research

“…25 Chen and coworkers coated a cyclosporine A loaded nanocarrier with an ACPP connected via an alternative MMP sensitive linker (PVGLIG) and studied the localization in controlled cortical impact injury mice (Table 2, entry 2). 26 The structures crossed the blood brain barrier and internalized into primary astrocytes and neurons at the lesion site. Cyclosporine A inhibits the opening of the mitochondrial permeability transition pore thereby preventing apoptosis.…”